Safety and efficacy of intravenous enoxaparin for carotid endarterectomy: A prospective randomized pilot trial

Article Outline

• Abstract
• Material and methods
  • Patient inclusion criteria
  • Patient exclusion criteria
  • Surgical procedure and anticoagulation
  • Blood collection and laboratory analyses
  • Assessment of end points
  • Statistical methods
• Results
• Discussion
• Conclusion
• Author contributions
• References
• Copyright

Objective

This prospective, randomized, single-center, open-label pilot study evaluated the safety and efficacy in carotid surgery of a single intraoperative bolus of body weight–adjusted enoxaparin compared with unfractionated heparin.

Methods

Symptomatic and asymptomatic patients with high-grade internal carotid artery stenosis were included. The primary objective was to evaluate perioperative efficacy (incidence of thromboembolic ischemic stroke). The secondary objective was to evaluate safety, including avoidance of hematoma at the site of surgery, gastrointestinal bleeding, rate of blood transfusions, and occurrence of heparin-induced thrombocytopenia.

Results

From July 2005 to June 2006, 338 consecutive patients undergoing carotid endarterectomy were enrolled; of these, 115 patients did not fulfill inclusion criteria, and 63 patients refused to participate. The remaining 160 patients were assigned in a 3:1 randomization to receive enoxaparin (0.5 mg/kg) or unfractionated heparin (5000 IU) intraoperatively as an intravenous bolus (120 and 40 patients, respectively). The mean patient age was 70.3 years (range, 43.3-94.7 years), and 54 were women. Internal carotid artery stenosis was asymptomatic in 55% and symptomatic in 45%. The difference in baseline characteristics between these groups was not significant. The rate of cerebral embolic events was 0.8% in the enoxaparin group (n = 1) and 2.5% in the unfractionated heparin group (n = 1). The rate of severe bleeding complications was 1.7% in the enoxaparin group (n = 2) and 5% in the unfractionated heparin group (n = 2; P > .05). No case of heparin-induced thrombocytopenia was observed.

Conclusion

This pilot study found no difference between enoxaparin and unfractionated heparin during carotid endarterectomy in perioperative bleeding or embolic events. A large multicenter trial seems to be warranted.

Anticoagulation is an elementary therapeutic modality in vascular surgery. The first anticoagulant medication used intraoperatively was unfractionated heparin (UFH),¹ a substance that has been almost universally applied until recently. Unfractionated heparin is used either as a standard intravenous bolus before arterial cross-clamping, usually 5000 IU,², ³, ⁴, ⁵ or as a body weight–adjusted dose. Although UFH is an effective antithrombotic agent, the anticoagulant response it produces in patients is highly variable and unpredictable.⁶ Thus, even body weight–adjusted application does not always yield the desired target anticoagulation. In contrast, low-molecular-weight heparins (LMWHs) seem to be superior, at least during percutaneous coronary interventions.⁷

Evidence for the beneficial effects of LMWH compared with UFH in vascular surgery is sparse. One prospective, randomized controlled trial for peripheral vascular surgery demonstrated that patients receiving the LMWH enoxaparin had a similar occlusion rate of the reconstructed arterial bed yet statistically significant less blood loss compared with an UFH group.² However, carotid endarterectomy was expressively excluded from the study.

Efficacy of anticoagulation during and after carotid endarterectomy is crucial because the brain is much less tolerant to embolic events than other tissues. Safety, on the other hand, is vital, because bleeding may result in postoperative morbidity and in some cases in fatal complications.

The present study was conducted as a pilot trial (before a planned randomized multicenter study) to estimate the efficacy and safety of a single intraoperative intravenous bolus of 0.5-mg/kg body weight–adjusted enoxaparin compared with 5000 IU of UFH in carotid surgery. This pilot trial was necessary because no reliable data on anticoagulation with LMWH in carotid surgery existed thus far.

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Material and methods 

This pilot study was a prospective, randomized, single-center, open-label evaluation of the safety and efficacy of body weight–adjusted enoxaparin compared with a fixed dose of UFH in carotid surgery. The primary study objective was to evaluate the efficacy of UFH, measured as the incidence of thromboembolic ischemic events during surgery and at 30 days of follow-up. The secondary objective was to evaluate safety, measured as avoidance of intraoperative and postoperative bleeding complications (hematoma at the site of surgery indicating surgical revision, gastrointestinal bleeding, and the rate of blood transfusion), the occurrence of heparin-induced thrombocytopenia (HIT), and death.

Patient inclusion criteria 

Symptomatic and asymptomatic patients with internal carotid artery (ICA) stenosis >70% according to North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria ⁸ were enrolled in the study. Internal carotid artery (ICA) stenosis was diagnosed by magnetic resonance angiography (MRA) and duplex ultrasound (DUS) imaging in all patients. Grading of ICA stenosis by DUS was performed according to previously published criteria measuring peak systolic velocity (PVS)⁹, ¹⁰:

All patients underwent preoperative and postoperative neurologic assessment and were scored according to the National Institute of Health Stroke Score (NIHSS).¹¹ Patients were assigned in a 3:1 randomization to receive either enoxaparin (0.5 mg/kg) or UFH (5000 IU) intraoperatively as an intravenous bolus (120 and 40 patients, respectively). The study was approved by the local ethics committee (EK 04-180-0105; EudraCT number: 2004-004762) and performed in accordance with the Declaration of Helsinki. All patients gave written informed consent.

Patient exclusion criteria 

Patients with a recent disabling stroke ipsilateral or contralateral, or both, to the side scheduled for surgery, patients with a pacemaker or implanted cardioverter/defibrillator, patients not tolerating locoregional anesthesia, and patients with uncontrolled arterial hypertension (blood pressure >200 mm Hg) at two successive readings were not included in the study. Also, patients with active bleeding disorders due to acquired or inherited coagulopathy, platelet counts <100 ×10⁹/L or >400 ×10⁹/L, recent thrombolytic therapy of any vascular bed (<2 weeks before surgery) or patients receiving dual antiplatelet therapy, clopidogrel monotherapy, not tolerating aspirin or taking oral anticoagulation were not considered as candidates to participate in the study. Patients with a documented episode of HIT or thrombosis, or both, and anemia (hemoglobin < 10 g/mL) were also excluded from the study.

Surgical procedure and anticoagulation 

The standard surgical technique for all patients was eversion endarterectomy. All patients were anesthetized by a C2-C3 cervical block using a 1% lidocaine suspension. After effective analgesia, a horizontal skin incision parallel to the mandible, using a skin crease, was performed. Five to 10 minutes before the ICA was cross-clamped, anticoagulation was performed according to the randomization list by either a single, weight-adjusted intravenous bolus of enoxaparin (0.5 mg/kg body weight; Sanofi-Aventis, Vienna, Austria) or UFH (5000 IU; Baxter Healthcare, Vienna, Austria).

Intraoperative completion angiography was done in all patients after endarterectomy and completion of the anastomosis. After meticulous hemostasis, a 12-Charriere suction drainage was placed at the anastomosis, and skin closure was completed by an intracutaneous, nonabsorbable suture. Only surgeons having the experience of ≥200 carotid endarterectomies during the last 5 years, and 50 during the year preceding the trial, were performing endarterectomies in this study.

Patients in both groups received 40 mg daily of enoxaparin subcutaneously on the days 1 to 3 after surgery; aspirin (oral 100 mg acetylsalicylic acid per day) was continued in all patients on the morning after surgery.

Blood collection and laboratory analyses 

Blood was drawn before and after operation by venipuncture of the antecubital vein and collected in standard serum and K3-ethylenediaminetetraacetic acid (EDTA) tubes (Vacuette EDTA Tubes, Greiner Bio-One, Kremsmünster, Austria). Analysis of levels of total cholesterol, high-density lipoprotein cholesterol, triglycerides, and serum creatinine was performed on a Hitachi 917 analyzer (Roche Diagnostics, Mannheim, Germany). Hemoglobin A_1c in K3-EDTA whole blood was analyzed on a Cobas Integra 700 analyzer (Roche Diagnostics, Basel, Switzerland). Routine hematology and chemistry analyses were performed ≤2 hours after venipuncture.

For intraoperative antifactor Xa measurements, blood was drawn from an indwelling catheter in the radial artery immediately before UFH/enoxaparin administration, and at 15, 30, and 45 minutes after heparinization. Blood was collected into a tube containing 3.2% trisodium citrate (Vacuette Tube, Greiner Bio-One), which was used to determine the activated partial thromboplastin time (aPTT) and antifactor Xa activity ≤2 hours after venipuncture. The aPTT was measured on a Sysmex CA7000 coagulation analyzer (Sysmex-Toa, Kobe, Japan) with Actin FS aPTT reagent supplied by Dade-Behring (Dade-Behring, Marburg, Germany). Levels of UFH- and enoxaparin-dependent antifactor Xa activity in plasma were measured with a commercial chromogenic assay (Biophen Heparin 6, Hyphen Biomed, Neuville-sur-Oise, France). The antifactor Xa activity assay was calibrated with either UFH or LMWH calibrators supplied by the manufacturer and performed on a STACompact coagulation analyzer (Roche Diagnostics GmbH, Mannheim, Germany).

Assessment of end points 

All patients underwent preoperative and postoperative assessment by an independent neurologist. Patients were scored according to the NIHSS. Patients who had an increase from the preoperative NIHSS underwent at least one cranial CT scan to assess morphologic changes of the brain. Transient ischemic attack (TIA) was defined as a neurologic deficit lasting <24 hours, and strokes were defined as central neurologic deficits lasting >24 hours.

Bleeding complications and occurrence of HIT were assessed by full blood counts at 4, 24, and 48 hours postoperatively as well as with tight clinical inspections. Heparin-induced thrombocytopenia was defined as a decrease in platelet count after heparin administration either by half or <100 ×10⁹/L.¹² Patients who fulfilled these criteria underwent antibody testing. Severe bleeding was defined as any postoperative bleeding indicating blood transfusion or surgical revision. Patients with rapidly growing swelling or airway compromise at the surgical site, or both, had emergency revision surgery.

Statistical methods 

The study was exploratory in nature and therefore not powered to demonstrate a particular treatment effect. Patients were assigned in a 3:1 randomization to receive either enoxaparin (0.5 mg/kg) or UFH (5000 IU) intraoperatively as an intravenous bolus (120 and 40 patients, respectively). The 3:1 randomization strategy was claimed by the local Ethics Committee for this pilot trial to estimate efficacy and safety of LMWH during carotid surgery because no relevant data on this question were available. This randomization mode was agreed upon with the Ethics Committee because the alternative would have been a comparison with historical controls. The planned sample size of 120 patients was sufficient to estimate the stroke rate using a 95% confidence interval (CI) with a precision of 3.3% if the true event rate was ≤3.5%. Consequently, if a stroke rate of 2.2% was observed in this study (as could be expected from earlier experience at the study center), the upper boundary of the 95% confidence interval would be <5.5% and therefore within the range of pertinent guidelines. The sample size of 40 for the control group was primarily chosen because of feasibility considerations and would allow for a test power of 80% in case the difference of stroke rates between groups were as extreme as 2.2% vs 20.4% at a two-sided 5% significance level. Randomization was according to an online protocol on the day of surgery.

Owing to the explorative nature of this study, descriptive summaries were primarily used. The primary efficacy analysis was based on the full analysis population and estimated the thromboembolic stroke rate ≤30 days of surgery using a 95% exact CI. The same method was applied for secondary thromboembolic end points (TIA, prolonged reversible ischemic neurologic deficit) and the overall thromboembolic event rate. Event rates between treatment groups were compared with χ² tests. Values of P ≤ .05 were considered significant.

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Results 

From July 2005 to June 2006, 338 consecutive patients undergoing carotid endarterectomy at our institution were screened for this study, of whom 115 patients (34%) did not fulfill inclusion criteria, and 63 refused to participate in a clinical trial (19%); thus, 160 of the consecutive patients (47%) were included. One-third of the 115 excluded patients represented acute carotids (TIA or stroke ≤24 hours), and most of the remaining patients were excluded because of intravenous or catheter-based lysis of different vascular beds ≤2 months, were taking dual antiplatelets, were already being treated with UFH or enoxaparin, or were taking oral anticoagulation. Because the Ethics Committee and the primary investigator were concerned to preclude inclusion of patients at excessive risk of mainly intracerebral bleeding due to the different anticoagulation effects of enoxaparin so far not addressed in a clinical trial for carotid surgery, these patients were not included in the study. A total of 160 patients underwent randomization; however, surgery was postponed for one woman in the enoxaparin group because she presented with cardiovascular symptoms on the day before surgery. Thus, the study comprised 159 patients, 119 in the enoxaparin group and 40 in the UFH group.

Demographic data and cardiovascular risk factors between the groups are listed in Table I. Of the included patients, 106 were men and 53 were women. Their mean age was 70.3 years (range, 43.3-94.7 years). The difference in demographic variables between the groups was not significant.

Table I. Demographic data and cardiovascular risk factors in patients undergoing carotid surgery

Variable	Enoxaparin	Unfractionated heparin	Pa
No.	119	40
Sex
Male	82	24
Female	37	16
Age, median (IRQ) y	71.2(64.3-76.3)	72.6(62.6-79.9)	0.71
Symptomatic ICA stenosis, %	42.7	52.5	0.29
Hypertension, %	90	85	0.39
Diabetes, %	18.5	20	0.83
Hyperlipidemia, %	63	67.5	0.61
Smokers, %	46	40	0.49

Table II presents the baseline laboratory values for both groups. All patients had normal red blood cell and platelet counts, and global coagulation indicators were within normal ranges. The serum creatinine level in all patients was <110 μmol/L. There was no significant difference in the laboratory variables between the groups.

Table II. Baseline laboratory values in patients undergoing carotid surgery

Variablea	Enoxaparin	Unfractionated heparin	Pb
Red blood cell counts, ×1012/L	4.3(4.0-4.6)	4.4(4.1/4.8)	0.81
Hemoglobin concentration, g/L	132(126-139)	133(126/138)	0.74
Hematokrit, /L	0.39(0.37-0.42)	0.39(0.37/0.42)	0.93
Platelet counts, ×109/L	234(197.5-279)	210(195.5/249.5)	0.65
Serum creatinine, μmol/L	79.6(70.7-88.4)	88.4(70.7/88.4)	0.72
Prothrombin time, %	89(84-94)	91(79/94)	0.83
APTT	26.0(24.0/28.0)	26.0(24.0/35.5)	0.91

APTT, Activated partial thromboplastin time.

Anticoagulation in the UFH group was performed by a fixed dose of UFH (5000 IU), representing a mean actual dose of 69.4 IU/kg body weight. The patients in the enoxaparin group received a body weight–adjusted bolus of enoxaparin of 0.5 mg/kg, representing a mean total dose of 38.0 mg. The Fig shows the anticoagulation effect of both types of heparins, as estimated by the antifactor Xa activities. Antifactor Xa levels were measured before and at 15, 30, and 45 minutes after enoxaparin or UFH administration. Sufficient anticoagulation was obtained with both enoxaparin and UFH; however, the antifactor Xa levels 15 minutes after the UFH injection were highly variable and were significantly higher than after enoxaparin 30 and 45 minutes after application.

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• Fig. 

  Course of the anticoagulation response before carotid surgery and after an intravenous (iv) bolus of unfractionated heparin (UNF) or low-molecular-weight heparin (LMWH) at 15, 30 and 45 minutes postoperatively as estimated by antifactor Xa activities (IU/mL). The solid line, enoxaparin (n = 119); dotted line, UNF (n = 40). Median values are presented with interquartile ranges (whiskers). ***P < .001; **P < .01 Kruskal-Wallis test.

For the four time points (before and 15, 30 and 45 minutes after) median antifactor Xa levels were 0.10 ± 0.07, 0.91 ± 0.32, 0.93 ± 0.26, and 0.85 ± 0.20 IU/mL in the enoxaparin group and 0.12 ± 0.13, 1.28 ± 0.78, 1.37 ± 0.41, and 1.23 ± 0.31 IU/mL in the UFH group. The statistical differences between the groups for the different time points were P = .8, P = .08, P = .0007, and P = .0028, respectively. Within groups, there was no significant difference between time points.

The occurrence of TIA and stroke was 1.3% for the whole study population (1 patient in the enoxaparin group, 0.8%; 1 patient in the UFH group, 2.5%; P = .4152; Table III). Two patients in each group needed surgical revision. One patient in the UFH group had bleeding from the margin of the skin incision, not compromising breathing or inducing swelling of the neck, and a single interrupted suture at bedside was sufficient to stop the bleeding.

Table III. Outcome end points of patients after carotid surgery

TIA, transient ischemic attack.

The incidence of severe bleeding complications was 2.5% for the whole study population: two patients in the enoxaparin group (1.7%) and two patients in the UFH group (5%; P = 0.35; Table IV). The body weight–adjusted doses of UFH for the three patients with bleeding complications were 62.5, 71, and 74 IU/kg, respectively. The antifactor Xa activity 30 minutes after infusion was 0.92, 1.09, and 0.96 U/mL, respectively, and at 4 hours was 0.71, 0.65, and 0.77 U/mL, respectively. The two patients with perioperative bleeding complications in the enoxaparin group had doses of 30 mg and 42 mg enoxaparin with antifactor Xa levels of 1.03 and 0.98 U/mL, respectively, 30 minutes after enoxaparin administration and 0.67 and 0.5 U/mL at 4 hours.

One patient died during follow-up of a myocardial infarction. After an uneventful postoperative course and discharge on day 5, she was readmitted on day 22 because of chest pain caused by an ultimately fatal myocardial infarction.

None of the patients presented with clinical or laboratory signs of HIT. Two patients in the UFH group required blood transfusions, both of which had a wound revision for hematoma. Preoperative median platelet counts (×10⁹/L) in the enoxaparin group were 234 (IRQ, 197.5-279) and in the UFH group 210 (IRQ, 195.5-249.5). Postoperative platelet counts were 199 (IRQ, 179-234) and 199 (177-233), respectively.

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Discussion 

Unfractionated heparin is the most widely used heparin in vascular surgery and endovascular interventions today; however, evidence is growing that the LMWHs, and among these enoxaparin, are as effective and in some cases safer than UFH.², ⁷ The current study comparing a single body weight–adjusted bolus of enoxaparin compared with fixed-dose UFH during carotid surgery—to our knowledge the first assessing LMWH in carotid surgery—corroborates these findings. In this pilot study, enoxaparin had comparable efficacy by means of anticoagulant effects and safety by means of occurrence of major bleeding complications. For carotid surgery, local bleeding complication at the surgical site indicating revision—usually as an emergency procedure due to airway compromise—is a serious complication causing considerable morbidity and mortality.

The enoxaparin dose of 0.5 mg/kg appeared to be as safe as a standard dose of UFH in the current study. Severe bleeding complications indicating surgical revision in the operating room were observed in 1.7% in the enoxaparin and in 5% in the UFH group; one patient only needed a single suture due to bleeding from the wound margin, adding up to 7.5% in the UFH group. These results are in keeping with results at our institution of 3% and are superior to the rate of severe bleeding complications in the literature, which is as high as 10.9%.¹³

All bleeding complications occurred and were treated before patients received their first postoperative subcutaneous enoxaparin dose. This is of relevance, because mixing UFH and enoxaparin may cause excessive bleeding complications. Such an effect has been reported for cardiac bypass surgery in relatively small sample sizes¹⁴ and also for percutaneous coronary revascularization.¹⁵ Investigators in the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial concluded that a modest increase of bleeding was observed when enoxaparin and UFH were combined; yet, when enoxaparin was used alone, it was suggested to be superior to UFH.

A fixed dose of 5000 IU of UFH was used in the current study because this represents a very common practice in vascular surgery², ³, ⁴, ⁵ and has been applied at our institution for >4000 carotid endarterectomies, with a 3% rate for surgical revision owing to local bleeding.¹⁶ The comparison of a fixed dose of UFH compared with a body weight–adjusted dose of LMWH may be a limitation of this study. One aim of this pilot trial, however, was to find an anticoagulant regimen that would overcome the somewhat improvable (although widely used) UFH protocol, which does not consider individual differences of heparin response of patients independent of adjusting for body weight. In fact, the used body weight–adjusted dose of enoxaparin resulted in antifactor Xa levels in the same range as with fixed-dose UFH, yet with less variability (Fig).

Nonspecific interactions of heparin with several plasma proteins also have the potential to limit the amount of heparin available to bind to antithrombin, rendering its anticoagulant effect quite unpredictable.¹⁷, ¹⁸, ¹⁹, ²⁰, ²¹ Thus, the frequently advocated body weight–adjusted heparinization does not appear to be particularly useful. It is also not clear which dose is optimal because 70 up to 100 IU/kg are used.²², ²³

Most important, for these regimens, antagonization with protamine was recommended, which is a potential cause for significant morbidity.²⁴ In this respect, however, UFH is superior to LMWH because the at least partial inability to reverse the effect of enoxaparin is frequently regarded as a serious limitation for its use in vascular surgery. Yet, protamine does neutralize antithrombin activities and approximately 60% of antifactor Xa activities in LMWH.²⁴ This finding is highlighted by the study of Norgren et al,² where protamine was used to reverse enoxaparin effects in patients with excessive intraoperative bleeding. Also important was that antagonization was used in the enoxaparin group significantly less than in the UFH group (3% vs 8%; P = .001). Thus, it appears that anticoagulation at a desired level and duration, in a highly reproducible fashion, requires less frequent reversing. Finally, pharmacokinetics of enoxaparin given intravenously differs considerably from its subcutaneous application.²⁵ When given intravenously, enoxaparin at 0.5 mg/kg reaches a desired anticoagulation for only up to 2 hours.²⁶

In the current study, the mean body weight–adjusted dose of UFH was 69.4 ± 12.7 IU/kg for all patients. The body weight–adjusted doses of heparin for the three patients with bleeding complications were 62.5, 71, and 74 IU/kg and thus well within the suggested range for optimal anticoagulation.

The dose of 0.5 mg/kg for enoxaparin seems to be efficient and safe because the stroke rate and bleeding rate were both comparable with these rates for UFH. The mean dose in our patient population was 38 ± 5.8 mg, and is thus comparable to the fixed dosing of 40 mg enoxaparin used by Norgren et al² for peripheral vascular surgery. The two patients with perioperative bleeding complications had received doses of 30 mg and 42 mg enoxaparin without a considerable elevation of the antifactor Xa levels.

Low-molecular-weight heparin exhibits considerably less nonspecific binding to plasma proteins than UFH,²⁷ and its anticoagulant response, as measured by antifactor Xa levels, is more predictable than for UFH.²⁶ Thus, body weight–adjusted dosing does appear to be more useful. All these effects imply that enoxaparin may be a more reliable and predictable alternative to UFH; however, comparing anticoagulation effects for these heparins is difficult. Antifactor Xa measurements are not optimal, especially for monitoring UFH, but in this study, the assay was calibrated for UFH.

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Conclusion 

Body weight–adjusted enoxaparin seems to be as effective and safe as UFH during carotid endarterectomy. On the basis of the results of the current pilot study, more than 800 patients would need to be randomized between the two regimens to estimate the superiority of one drug over the other in a clinical trial.

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Author contributions 

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